ABSTRACT While Fc receptors (FcRs) for switched immunoglobulin isotypes have been extensively characterized, an FcR for IgM (Fc&#956;R) has defied genetic identification. By retroviral expression and functional cloning, we have recently identified a cDNA encoding a bona fide Fc&#956;R. The FCMR gene encodes a type I membrane protein with the following features: an extracellular region with a single V-set Ig-like domain that has homology to the polymeric Ig receptor (pIgR) and the FcR for IgA and IgM (Fc&#945;/&#956;R), a transmembrane segment, and a relatively long cytoplasmic tail containing conserved serine and tyrosine residues. Fc&#956;R is defined as an ~60 kDa transmembrane sialoglycoprotein with exclusive and high affinity binding specificity for the Fc portion of IgM. Unlike other FcRs, the major cell types expressing Fc&#956;R are adaptive immune cells, both B and T lymphocytes. Although this receptor was initially designated as Fas apoptotic inhibitory molecule 3 (FAIM3) or TOSO, our results clearly indicate that Fc&#956;R per se has no inhibitory activity in Fas-mediated apoptosis and that such inhibition is only achieved when anti-Fas antibody of IgM, but not IgG, isotype is used for inducing apoptosis. Based on these findings, together with Fc&#956;R-specific antibodies and Fcmr-deficient mice that we have developed, we will be able to define mechanisms by which the Fc&#956;R can regulate the immune system. We hypothesize that Fc&#956;R regulates immune responses by binding to IgM antibodies and IgM/antigen immune complexes. This hypothesis will be tested through the following Specific Aims: 1) Expand our recently published initial characterization of the Fc&#956;R to more precisely define: (a) its cellular distribution and how its surface expression is regulated, (b) the biochemical events that occur after ligand binding, and (c) its potential association with other membrane proteins;2) Determine the functional potential of the Fc&#956;R in B cells;3) Employ an Fcmr-deficient mouse model to explore the in vivo function of the Fc&#956;R. The data generated from these studies could provide insights into strategies for vaccine development, therapies for inflammatory, autoimmune and immunodeficient disorders, and the pathogenesis of hematological malignancies.